Although many drugs are known that kill cancer cells, there are apparently none that can eradicate solid tumors at doses that are not lethal to the patient. Metastatic tumors are even more difficult to treat. Therefore, there is an advantage in cancer treatment to target the drug specifically to the tumor or metastasis. In this way, side effects, which occur at sites away from the tumor, can be suppressed.
Targeting requires a means of creating a therapeutically effective amount of active drug locally at the tumor site and at the same time reducing systemic administration. One strategy is to mask the drug as an inactive prodrug that is unmasked by some special property of the target cells. Denmeade, S. R., et al. Cancer Research 58, 2537-2540 (1998).
It is metastasis, more than any other phenomenon, that makes cancer a killer. Tumors that do not metastasize are usually curable by surgery, but those that do have a generally poor prognosis, even with chemotherapy that is effective against cells of the primary. Thus drugs that can easily kill most of a 109-cell primary tumor are ineffective against metastatic tissue of only 1000 cells. It has been indicated that long-term survival for phases 2 and 3 of breast carcinoma (positive lymph nodes) are <10% even with chemotherapy, whereas for phase 1 (no positive lymph nodes) survival is >70% (McGuire, N.E.J.M. 320, 525 (1989).), often with no chemotherapy.
Clearly, metastatic cells are not just bits of the primary tumor. Instead, they arise from a tiny subpopulation that has the special powers of breaking away, surviving during transit in a hostile environment, lodging somewhere, penetrating basement membrane into a safe haven, and attracting its own blood supply (Fidler, Cancer Res. 50, 6130 (1990); Kerbel, Int. J. Cancer 47, 118 (1991). Micrometastes are those which do not have angiogenesis, i.e., the capacity to have their own blood supply.
Metastases are known to secrete a variety of hydrolytic enzymes not normally secreted at noncancer sites for the purpose of penetrating basement membrane. Most prominent among these enzymes is Collagenase IV (Goldfarb, Sem. Thromb. Hemostasis 12, 294 (1986); Hendrix, Molec. Cell. Probes 6, 59 (1992), which is also secreted by primary tumor cells. Until recently, this enzyme was not used for targeting because of the lack of good small-molecule substrates, but recently it was reported that Gly-Phe-Ala-Leu linked to polymer was cleaved rapidly by this enzyme (De Marre, J. Controlled Release 36, 87 (1995).
Another enzyme recently implicated in tumor invasion is elastase. Starcher, J. Invest. Derm. (1996), 107, 159. Peptide motifs which this enzyme binds and cleaves include X-Ala-Ala-Pro-Val (SEQ ID NO: 1) or X-Ala-Ala-Pro-Nva-(SEQ ID NO:2) where X is a peptide amino capping group and Nva is norvaline.
A potential way to intensify the enzymatic unmasking of drug specifically by metastatic cells is to take advantage of their special property to binding to basement membrane. Two peptide motifs which these cells have been found to bind to be useful as an adhesion peptide are Tyr-Ile-Gly-Ser-Arg (SEQ ID NO:3) and Gly-Arg-Gly-Asp-Ser (SEQ ID NO:4). Saiki, Clin. Immunother. 1, 307 (1994).
Totally lacking in the art, are prodrugs and methods to prolong contact time of a cytotoxic compound specifically with metastasizing cells, affording more efficient hydrolysis.